FR2903102A1 - NOVEL NAPHTHALENIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents
NOVEL NAPHTHALENIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME Download PDFInfo
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
Abstract
Composés de formule (I) : Médicaments.Compounds of formula (I): Drugs.
Description
-1- La présente invention concerne de nouveaux dérivés naphtaléniques,The present invention relates to novel naphthalenic derivatives,
leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. Les composés de la présente invention sont nouveaux et présentent des caractéristiques pharmacologiques très intéressantes concernant les récepteurs mélatoninergiques. their preparation process and the pharmaceutical compositions containing them. The compounds of the present invention are novel and have very interesting pharmacological characteristics concerning melatoninergic receptors.
De nombreuses études ont mis en évidence ces dix dernières années le rôle capital de la mélatonine (N-acétyl-5-méthoxytryptamine) dans de nombreux phénomènes physiopathologiques ainsi que dans le contrôle des rythmes circadiens. Toutefois, elle possède un temps de demi-vie assez faible dû à une rapide métabolisation. Il est donc très intéressant de pouvoir mettre à la disposition du clinicien des analogues de la mélatonine, lo métaboliquement plus stables et présentant un caractère agoniste ou antagoniste, dont on peut attendre un effet thérapeutique supérieur à celui de l'hormone elle-même. Outre leur action bénéfique sur les troubles du rythme circadien (J. Neurosurg. 1985, 63, pp. 321-341) et du sommeil (Psychopharmacology, 1990, 100, pp. 222-226), les ligands du système mélatoninergique possèdent d'intéressantes propriétés pharmacologiques sur le 15 système nerveux central, notamment anxiolytiques et antipsychotiques (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), analgésiques (Pharmacopsychiat., 1987, 20, pp. 222-223), ainsi que pour le traitement des maladies de Parkinson (J. Neurosurg. 1985, 63, pp. 321-341) et d'Alzheimer (Brain Research, 1990, 528, pp. 170-174). De même, ces composés ont montré une activité sur certains cancers 20 (Melatonin -Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), sur l'ovulation (Science 1987, 227, pp. 714-720), sur le diabète (Clinical Endocrinology, 1986, 24, pp. 359-364), et dans le traitement de l'obésité (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446). Ces différents effets s'exercent par l'intermédiaire de récepteurs spécifiques de la 25 mélatonine. Des études de biologie moléculaire ont montré l'existence de plusieurs sous-types réceptoriels pouvant lier cette hormone (Trends Pharmacol. Sci., 1995, 16, p. 50 ; WO 97.04094). Certains de ces récepteurs ont pu être localisés et caractérisés pour différentes espèces, dont les mammifères. Afin de pouvoir mieux comprendre les fonctions physiologiques de ces récepteurs, il est d'un grand intérêt de disposer de ligands sélectifs. 2903102 -2- De plus, de tels composés, en interagissant sélectivement avec l'un ou l'autre de ces récepteurs, peuvent être pour le clinicien d'excellents médicaments pour le traitement des pathologies liées au système mélatoninergique, dont certaines ont été mentionnées précédemment. 5 Les composés de la présente invention outre leur nouveauté, montrent une très forte affinité pour les récepteurs de la mélatonine. Ils présentent par ailleurs une forte affinité pour le récepteur 5-HT2c, ce qui a pour effet de renforcer les propriétés observées avec les récepteurs mélatoninergiques, notamment dans le domaine de la dépression. Numerous studies have highlighted over the last ten years the important role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena as well as in the control of circadian rhythms. However, it has a relatively low half-life due to rapid metabolism. It is therefore very interesting to be able to provide the clinician with melatonin analogues which are metabolically more stable and have an agonist or antagonist character, from which a therapeutic effect superior to that of the hormone itself can be expected. In addition to their beneficial effect on circadian rhythm disorders (J. Neurosurg, 1985, 63, pp. 321-341) and sleep (Psychopharmacology, 1990, 100, pp. 222-226), the melatoninergic system ligands possess interesting pharmacological properties on the central nervous system, including anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), analgesics (Pharmacopsychiat., 1987, 20, pp. 222-223). ), as well as for the treatment of Parkinson's diseases (J. Neurosurg, 1985, 63, pp. 321-341) and Alzheimer's (Brain Research, 1990, 528, pp. 170-174). Likewise, these compounds have shown activity on certain cancers (Melatonin-Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), on ovulation (Science 1987, 227, pp. 714-720), on diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446). These different effects are mediated through specific receptors for melatonin. Molecular biology studies have shown the existence of several receptor subtypes capable of binding this hormone (Trends Pharmacol Sci., 1995, 16, p.50, WO 97.04094). Some of these receptors could be localized and characterized for different species, including mammals. In order to better understand the physiological functions of these receptors, it is of great interest to have selective ligands. Moreover, such compounds, by selectively interacting with either of these receptors, may be for the clinician excellent drugs for the treatment of pathologies related to the melatoninergic system, some of which have been mentioned. previously. The compounds of the present invention, in addition to being novel, show a very high affinity for melatonin receptors. They also have a high affinity for the 5-HT2c receptor, which has the effect of reinforcing the properties observed with melatoninergic receptors, particularly in the field of depression.
La présente invention concerne plus particulièrement le composé de formule (I) : OH O Me NH (I) ses énantiomères, ainsi que ses sels d'addition à une base pharmaceutiquement acceptable. Parmi les bases pharmaceutiquement acceptables, on peut citer à titre non limitatif l'hydroxyde de sodium, l'hydroxyde de potassium, la triéthylamine, la tertbutylamine, etc. The present invention more particularly relates to the compound of formula (I): ## STR2 ## and its addition salts with a pharmaceutically acceptable base. Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, and the like.
Encore plus particulièrement, l'invention concerne les composés qui sont le N-[3-hydroxy- 2-(7-méthox y- 1 -naphtyl)propyl]prop anamide, le N-[(2S)-3-hydroxy-2-(7-méthoxy-1-naphtyl)propyl]propanamide, et le N-[(2R)-3-hydroxy-2-(7-méthoxy-l-naphtyl)propyl] propanamide. Les sels d'addition à une base pharmaceutiquement acceptable des composés préférés de 20 l'invention font partie intégrante de l'invention. 2903102 -3-L'invention s'étend également au procédé de préparation des composés de formule (I) caractérisé en ce que l'on utilise comme produit de départ le composé de formule (II) : Me que l'on soumet en milieu basique à l'action du carbonate de diméthyle pour conduire au 5 composé de formule (III) : que l'on soumet à une réduction en présence d'hydrure pour conduire au composé de formule (IV) : OH NH2 10 sur lequel on condense le chlorure de propanoyle pour conduire au composé de formule (I), qui peut être purifié selon une technique classique de séparation, que l'on transforme, si on le souhaite, en ses sels d'addition à une base pharmaceutiquement acceptable et dont les énantiomères peuvent être séparés sur colonne chirale selon une technique classique de séparation. 2903102 -4- L'étude pharmacologique des dérivés de l'invention a montré qu'ils étaient atoxiques, doués d'une forte affinité sélective pour les récepteurs de la mélatonine et possédaient d'importantes activités sur le système nerveux central et, en particulier, on a relevé des propriétés thérapeutiques sur les troubles du sommeil, des propriétés antidépressives, 5 anxiolytiques, antipsychotiques, analgésiques ainsi que sur la microcirculation, qui permettent d'établir que les produits de l'invention sont utiles dans le traitement du stress, des troubles du sommeil, de l'anxiété, des dépressions saisonnières ou de la dépression majeure, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, de la schizophrénie, des attaques de 10 panique, de la mélancolie, des troubles de l'appétit, de l'obésité, de l'insomnie, des troubles psychotiques, de l'épilepsie, du diabète, de la maladie de Parkinson, de la démence sénile, des divers désordres liés au vieillissement normal ou pathologique, de la migraine, des pertes de mémoire, de la maladie d'Alzheimer, ainsi que dans les troubles de la circulation cérébrale. Dans un autre domaine d'activité, il apparaît que dans le traitement, 15 les produits de l'invention peuvent être utilisés dans les dysfonctionnements sexuels, qu'ils possèdent des propriétés d'inhibiteurs de l'ovulation, d'immmunomodulateurs et qu'ils sont susceptibles d'être utilisés dans le traitement des cancers. Les composés seront utilisés de préférence dans les traitements de la dépression majeure, des dépressions saisonnières, des troubles du sommeil, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, des troubles de l'appétit et de l'obésité. Par exemple, les composés seront utilisés dans le traitement de la dépression majeure, des dépressions saisonnières et des troubles du sommeil. La présente invention a également pour objet les compositions pharmaceutiques contenant 25 au moins un composé de formule (I) seul ou en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables. Parmi les compositions pharmaceutiques selon l'invention, on pourra citer, plus particulièrement celles qui conviennent pour l'administration orale, parentérale, nasale, per 2903102 -5- ou transcutanée, rectale, perlinguale, oculaire ou respiratoire et notamment les comprimés simples ou dragéifiés, les comprimés sublinguaux, les sachets, les paquets, les gélules, les glossettes, les tablettes, les suppositoires, les crèmes, les pommades, les gels dermiques, et les ampoules buvables ou injectables. Even more particularly, the invention relates to the compounds which are N- [3-hydroxy-2- (7-methoxy-1-naphthyl) propyl] prop anamide, N - [(2S) -3-hydroxy-2 - (7-methoxy-1-naphthyl) propyl] propanamide, and N - [(2R) -3-hydroxy-2- (7-methoxy-1-naphthyl) propyl] propanamide. The addition salts with a pharmaceutically acceptable base of the preferred compounds of the invention form an integral part of the invention. The invention also extends to the process for the preparation of the compounds of formula (I), characterized in that the compound of formula (II): Me which is subjected in the medium is used as starting material. basic to the action of dimethyl carbonate to give the compound of formula (III): which is subjected to reduction in the presence of hydride to yield the compound of formula (IV): OH NH 2 10 on which is condensed propanoyl chloride to give the compound of formula (I), which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable base and whose enantiomers can be separated on a chiral column according to a conventional separation technique. The pharmacological study of the derivatives of the invention has shown that they are atoxic, endowed with a high selective affinity for the melatonin receptors and have important activities on the central nervous system and, in particular, Therapeutic properties have been found on sleep disorders, antidepressant, anxiolytic, antipsychotic, analgesic and microcirculatory properties which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depression or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy , appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, e Parkinson's, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as disorders of the cerebral circulation. In another field of activity, it appears that in the treatment, the products of the invention can be used in sexual dysfunctions, that they possess properties of ovulation inhibitors, immunomodulators and that they are likely to be used in the treatment of cancers. The compounds will preferably be used in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity. For example, the compounds will be used in the treatment of major depression, seasonal depression and sleep disorders. The present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention, mention may be made, more particularly, of those which are suitable for oral, parenteral, nasal, transdermal, rectal, perlingual, ocular or respiratory administration and in particular simple or sugar-coated tablets. , sublingual tablets, sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
5 La posologie varie selon le sexe, l'âge et le poids du patient, la voie d'administration, la nature de l'indication thérapeutique, ou des traitements éventuellement associés et s'échelonne entre 0,01 mg et 1 g par 24 heures en une ou plusieurs prises. Les exemples suivants illustrent l'invention et ne la limitent en aucune façon. Exemple 1 : N-13-Hydroxy-2-(7-méthoxy-1-naphtyl)propyllpropanamide 10 Stade A : Cyano(7-méthoxy-l-naphtyl)acétate de méthyle Le (7-méthoxy-napht-1-yl)acétonitrile (20 g) est dissous dans 150 ml de tétrahydrofurane anhydre. L'hydrure de sodium (202,8 mmol) est ajouté à température ambiante, et le milieu est chauffé à reflux pendant 30 minutes. Le carbonate de diméthyle (12 ml) est ajouté avec précaution et le milieu réactionnel est chauffé à reflux pendant 30 minutes. Le milieu est 15 versé dans l'eau glacée et la phase aqueuse est acidifiée avec 21 ml d'une solution d'acide chlorhydrique à 37 % puis extraite par 2 fois 100 ml d'éther. La phase organique est lavée à l'eau, séchée, décolorée et évaporée. L'huile obtenue précipite dans l'éther et le précipité formé est essoré puis recristallisé pour conduire au produit du titre sous la forme d'un solide blanc.The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments and ranges from 0.01 mg to 1 g per 24 hours. hours in one or more takes. The following examples illustrate the invention and do not limit it in any way. Example 1: N-13-Hydroxy-2- (7-methoxy-1-naphthyl) propyllpropanamide Step A: Methyl cyano (7-methoxy-1-naphthyl) acetate (7-Methoxy-naphth-1-yl) Acetonitrile (20 g) is dissolved in 150 ml of anhydrous tetrahydrofuran. Sodium hydride (202.8 mmol) is added at room temperature, and the medium is refluxed for 30 minutes. Dimethyl carbonate (12 ml) is carefully added and the reaction medium is refluxed for 30 minutes. The medium is poured into ice water and the aqueous phase is acidified with 21 ml of a 37% hydrochloric acid solution and then extracted twice with 100 ml of ether. The organic phase is washed with water, dried, decolorized and evaporated. The oil obtained precipitates in ether and the precipitate formed is filtered off and then recrystallized to yield the title product in the form of a white solid.
20 Point de fusion : 80-82 C Stade B : 3-Amino-2-(7-méthoxy-l-naphtyl)-1-propanol, chlorhydrate Le chlorure d'aluminium (80 mmol), solubilisé dans 200 ml d'éther anhydre, est ajouté à une suspension d'hydrure mixte d'aluminium et de lithium à 0 C dans 300 ml d'éther anhydre. Après 10 minutes d'agitation le composé obtenu au Stade A (20 mmol) est ajouté 2903102 -6- en solution dans 200 ml d'éther anhydre. Après 30 minutes, le milieu est hydrolysé à froid et avec précaution avec une solution de soude (10 g ; 40 ml). Le précipité formé est ensuite filtré et abondamment lavé à l'éther. Le résidu obtenu après évaporation est repris par l'eau et la phase aqueuse est extraite au dichlorométhane. La phase organique est ensuite lavée à 5 l'eau, séchée, décolorée, puis traitée par l'acide chlorhydrique gazeux et évaporée. L'huile obtenue précipite dans l'acétate d'éthyle et le précipité formé est essoré puis recristallisé pour conduire au produit du titre sous la forme d'un solide blanc. Point de fusion : 164-166 C Stade C : N-[3-Hydroxy-2-(7-méthoxy-l-naphtyl)propyl]propanamide 10 Le composé obtenu au Stade B (3,73 mmol) est mis en solution dans 100 ml d'un mélange eau-acétate d'éthyle (50/50). Le carbonate de potassium (11,2 mmol) est ajouté et le milieu réactionnel est refroidi à 0 C avec un bain de glace. Le chlorure de propanoyle (4,6 mmol) est ajouté goutte à goutte et le milieu est agité pendant 15 minutes à froid. En fin de réaction, la phase organique est lavée avec une solution d'acide chlorhydrique (1M), lavée 15 à l'eau, séchée et évaporée sous pression réduite. Le solide obtenu est recristallisé dans de l'acétonitrile pour conduire au produit du titre sous la forme d'un solide blanc. Point de fusion : 128-129 C Microanalvse élémentaire : % C H N 20 Calculé : 71,05 7,36 4, 77 Trouvé : 70,82 7,39 4, 70 Le composé obtenu dans l'Exemple 1 est purifié sur colonne chirale pour conduire aux Exemples 2 et 3 : Exemple 2 : N-[(2S)-3-Hydroxy-2-(7-méthoxy-1-naphtyl)propyl]propanamide Exemple 3 : N-[(2R)-3-Hydroxy-2-(7-méthoxy-l-naphtyl)propyl]propanamide 2903102 -7 ETUDE PHARMACOLOGIQUE EXEMPLE A : Etude de la toxicité aiguë La toxicité aiguë a été appréciée après administration orale à des lots de 8 souris (26 2 grammes). Les animaux ont été observés à intervalles réguliers au cours de la 5 première journée et quotidiennement pendant les deux semaines suivant le traitement. La DL 50, entraînant la mort de 50 % des animaux, a été évaluée et a montré la faible toxicité des composés de l'invention. EXEMPLE B : Test de la nage forcée Les composés de l'invention sont testés dans un modèle comportemental, le test de la nage 10 forcée. L'appareil est constitué d'un cylindre en plexiglas rempli d'eau. Les animaux sont testés individuellement pendant une session de 6 minutes. Au début de chaque test, l'animal est placé au centre du cylindre. Le temps d'immobilisation est enregistré. Chaque animal est jugé immobile quand il cesse de se débattre, et reste à la surface de l'eau, immobile, ne 15 faisant seulement que les mouvements lui permettant de maintenir la tête hors de l'eau. Après administration 40 minutes avant le début du test, les composés de l'invention diminuent de façon significative la durée d'immobilisation attestant de leur activité antidépressive. 2903102 -8 EXEMPLE C : Etude de liaison aux réce i teurs MTl et MT2 de la mélatonine Les expériences de liaison aux récepteurs MT1 ou MT2 sont réalisées en utilisant la 2-[125I]-iodomélatonine comme radioligand de référence. La radioactivité retenue est déterminée à l'aide d'un compteur à scintillation liquide.Melting point: 80 ° -82 ° C. Step B: 3-Amino-2- (7-methoxy-1-naphthyl) -1-propanol, hydrochloride Aluminum chloride (80 mmol), solubilized in 200 ml of ether anhydrous, is added to a suspension of mixed hydride of aluminum and lithium at 0 ° C. in 300 ml of anhydrous ether. After stirring for 10 minutes the compound obtained in Step A (20 mmol) is added in solution in 200 ml of anhydrous ether. After 30 minutes, the medium is cold-hydrolyzed and carefully with a sodium hydroxide solution (10 g, 40 ml). The precipitate formed is then filtered and extensively washed with ether. The residue obtained after evaporation is taken up in water and the aqueous phase is extracted with dichloromethane. The organic phase is then washed with water, dried, decolorized, then treated with gaseous hydrochloric acid and evaporated. The oil obtained precipitates in ethyl acetate and the precipitate formed is filtered off and then recrystallized to yield the title product in the form of a white solid. Melting point: 164-166 ° C. Stage C: N- [3-Hydroxy-2- (7-methoxy-1-naphthyl) propyl] propanamide The compound obtained in Stage B (3.73 mmol) is dissolved in 100 ml of a mixture of water and ethyl acetate (50/50). Potassium carbonate (11.2 mmol) is added and the reaction mixture is cooled to 0 ° C. with an ice bath. Propanoyl chloride (4.6 mmol) is added dropwise and the medium is stirred for 15 minutes under cold conditions. At the end of the reaction, the organic phase is washed with a hydrochloric acid solution (1M), washed with water, dried and evaporated under reduced pressure. The solid obtained is recrystallized from acetonitrile to yield the title product as a white solid. Melting point: 128-129 ° C. Elemental microanalysis:% CHN Calculated: 71.05 7.36 4.17 Found: 70.82 7.39 4.70 The compound obtained in Example 1 is purified on a chiral column to give proceed to Examples 2 and 3: Example 2: N - [(2S) -3-Hydroxy-2- (7-methoxy-1-naphthyl) propyl] propanamide Example 3: N - [(2R) -3-Hydroxy-2 - (7-methoxy-1-naphthyl) propyl] propanamide 2903102 -7 PHARMACOLOGICAL STUDY EXAMPLE A: Acute Toxicity Study Acute toxicity was assessed after oral administration to batches of 8 mice (26 2 grams). The animals were observed at regular intervals during the first day and daily for two weeks after treatment. The LD 50, resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention. EXAMPLE B: Forced Swimming Test The compounds of the invention are tested in a behavioral model, the forced swim test. The apparatus consists of a Plexiglas cylinder filled with water. The animals are tested individually during a 6-minute session. At the beginning of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it ceases to struggle, and remains on the surface of the water, motionless, only making only the movements allowing it to keep its head out of the water. After administration 40 minutes before the start of the test, the compounds of the invention significantly reduce the duration of immobilization attesting to their antidepressant activity. EXAMPLE C: MT1 and MT2 receptor binding study of melatonin The MT1 or MT2 receptor binding experiments were performed using 2- [125 I] -iodomelatonin as a reference radioligand. The retained radioactivity is determined using a liquid scintillation counter.
5 Des expériences de liaison compétitive sont ensuite réalisées en triple, avec les différents composés à tester. Une gamme de concentrations différentes est testée pour chaque composé. Les résultats permettent de déterminer les affinités de liaison des composés testés (Ki). A titre d'exemple, le composé obtenu dans l'Exemple 1 présente un K;(MT1) de 1,4 nM, et 10 un K;(MT2) de 3,2 nM. EXEMPLE D : Etude de la liaison aux récepteurs sérotoninergiques 5-HT L'affinité des composés pour le récepteur humain 5-HT2c est évaluée sur des préparations membranaires de cellules CHO exprimant de façon stable ce récepteur. L'incubation est réalisée dans du tampon TRIS 50 mM, pH 7,4 contenant du MgC12 10 15 mM et de la BSA 0,1%, en présence de [3H]Mésulergine (1 nM) et de 25 fmol/ml de récepteur. La liaison non-spécifique est déterminée en présence de miansérine 10 M. La réaction est stoppée par l'ajout de tampon TRIS 50 mM, pH 7,4 suivi d'une étape de filtration et de 3 rinçages successifs : la radioactivité liée aux membranes restant sur les filtres (GF/B prétraités au PEI 0.1%) est comptée en scintillation liquide.Competitive binding experiments are then performed in triplicate, with the various compounds to be tested. A range of different concentrations is tested for each compound. The results make it possible to determine the binding affinities of the compounds tested (Ki). By way of example, the compound obtained in Example 1 has a K (MT1) of 1.4 nM and a K (MT2) of 3.2 nM. EXAMPLE D: Serotonin 5-HT receptor binding study The affinity of the compounds for the human 5-HT 2c receptor is evaluated on membrane preparations of CHO cells stably expressing this receptor. Incubation was performed in 50 mM TRIS buffer pH 7.4 containing 15 mM MgCl2 and 0.1% BSA in the presence of [3 H] mesulergine (1 nM) and 25 fmol / ml receptor. . The non-specific binding is determined in the presence of 10 M mianserine. The reaction is stopped by the addition of 50 mM TRIS buffer, pH 7.4 followed by a filtration step and 3 successive rinses: membrane-bound radioactivity remaining on the filters (GF / B pretreated with 0.1% PEI) is counted as liquid scintillation.
20 Les résultats obtenus montrent que les composés de l'invention sont affins pour le récepteur 5-HT2c avec des K; < 10 M. 2903102 -9- EXEMPLE E : Action des composés de l'invention sur les rythmes circadiens d'activité locomotrice du rat L'implication de la mélatonine dans l'entraînement, par l'alternance jour/nuit, de la plupart des rythmes circadiens physiologiques, biochimiques et comportementaux a permis 5 d'établir un modèle pharmacologique pour la recherche de ligands mélatoninergiques. Les effets des molécules sont testés sur de nombreux paramètres et, en particulier, sur les rythmes circadiens d'activité locomotrice qui représentent un marqueur fiable de l'activité de l'horloge circadienne endogène. Dans cette étude, on évalue les effets de telles molécules sur un modèle expérimental 10 particulier, à savoir le rat placé en isolement temporel (obscurité permanente). Protocole expérimental Des rats mâles âgés de un mois sont soumis dès leur arrivée au laboratoire à un cycle lumineux de 12h de lumière par 24h (LD 12 : 12). Après 2 à 3 semaines d'adaptation, ils sont placés dans des cages équipées d'une roue 15 reliée à un système d'enregistrement afin de détecter les phases d'activité locomotrice et de suivre ainsi les rythmes nycthéméraux (LD) ou circadiens (DD). Dès que les rythmes enregistrés témoignent d'un entraînement stable par le cycle lumineux LD 12 : 12, les rats sont mis en obscurité permanente (DD). Deux à trois semaines plus tard, lorsque le libre-cours (rythme reflétant celui de l'horloge 20 endogène) est clairement établi, les rats reçoivent une administration quotidienne de la molécule à tester. 2903102 - 10 - Les observations sont réalisées grâce à la visualisation des rythmes d'activité : - entraînement des rythmes d'activité par le rythme lumineux, - disparition de l'entraînement des rythmes en obscurité permanente, - entraînement par l'administration quotidienne de la molécule ; effet transitoire ou durable.The results obtained show that the compounds of the invention are affine for the 5-HT2c receptor with K; EXAMPLE E Action of the Compounds of the Invention on the Circadian Rhythms of Rat Locomotor Activity The involvement of melatonin in the training, by day / night alternation, of most physiological, biochemical and behavioral circadian rhythms have made it possible to establish a pharmacological model for the search for melatoninergic ligands. The effects of the molecules are tested on many parameters and, in particular, on the circadian rhythms of locomotor activity that represent a reliable marker of endogenous circadian clock activity. In this study, the effects of such molecules are evaluated on a particular experimental model, namely the rat placed in temporal isolation (permanent darkness). Experimental protocol Male rats aged one month are subjected to a light cycle of 12 hours of light per day as soon as they arrive at the laboratory (LD 12:12). After 2 to 3 weeks of adaptation, they are placed in cages equipped with a wheel 15 connected to a recording system in order to detect the phases of locomotor activity and thus follow the nycthemeral (LD) or circadian rhythms ( DD). As soon as the recorded rhythms show steady training by the LD 12: 12 light cycle, the rats are put in permanent darkness (DD). Two to three weeks later, when the free-course (rhythm reflecting that of the endogenous clock) is clearly established, the rats receive a daily administration of the molecule to be tested. 2903102 - 10 - The observations are made thanks to the visualization of the rhythms of activity: - training of the rhythms of activity by the light rhythm, - disappearance of the training of the rhythms in permanent darkness, - training by the daily administration of the molecule; transient or lasting effect.
5 Un logiciel permet : - de mesurer la durée et l'intensité de l'activité, la période du rythme chez les animaux en libre cours et pendant le traitement, - de mettre éventuellement en évidence par analyse spectrale l'existence de composants circadiens et non circadiens (ultradiens par exemple). 1 o Résultats Il apparaît clairement que les composés de l'invention permettent d'agir de façon puissante sur le rythme circadien via le système mélatoninergique. EXEMPLE F : Test des cages claires/obscures Les composés de l'invention sont testés dans un modèle comportemental, le test des cages 15 claires/obscures, qui permet de révéler l'activité anxiolytique des molécules. L'appareil est composé de deux boîtes en polyvinyle couvertes de Plexiglas. L'une de ces boîtes est obscure. Une lampe est placée au-dessus de l'autre boîte donnant une intensité lumineuse au centre de celle-ci d'approximativement 4000 lux. Un tunnel opaque en plastique sépare la boîte claire de la boîte sombre. Les animaux sont testés 20 individuellement pendant une session de 5 min. Le plancher de chaque boîte est nettoyé entre chaque session. Au début de chaque test, la souris est placée dans le tunnel, face à la boîte sombre. Le temps passé par la souris dans la boîte éclairée et le nombre de transitions à travers le tunnel sont enregistrés après la première entrée dans la boîte sombre. 2903102 -11- Après administration des composés 30 min avant le début du test, les composés de l'invention augmentent de façon significative le temps passé dans la cage éclairée ainsi que le nombre des transitions, ce qui montre l'activité anxiolytique des dérivés de l'invention. EXEMPLE G : Composition pharmaceutique : Comprimés 5 1000 comprimés dosés à 5 mg de N-[3-hydroxy-2-(7-méthoxy-1-naphtyl)propyl] propanamide (Exemple 1) 5 g Amidon de blé 20 g Amidon de maïs 20 g Lactose 30 g 10 Stéarate de magnésium 2 g Silice 1 g Hydroxypropylcellulose 2 gSoftware allows: - to measure the duration and the intensity of the activity, the period of the rhythm in the animals in free course and during the treatment, - to possibly highlight by spectral analysis the existence of circadian components and non-circadian (ultradian for example). Results It is clear that the compounds of the invention make it possible to act in a powerful way on the circadian rhythm via the melatoninergic system. EXAMPLE F Light / Dark Cages Test The compounds of the invention are tested in a behavioral model, the clear / dark cages test, which reveals the anxiolytic activity of the molecules. The device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. One lamp is placed above the other box giving a luminous intensity in the center of it of approximately 4000 lux. An opaque plastic tunnel separates the clear box from the dark box. The animals are individually tested during a 5 min session. The floor of each box is cleaned between each session. At the beginning of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lighted box and the number of transitions through the tunnel are recorded after the first entry in the dark box. After administration of the compounds 30 min before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of transitions, which shows the anxiolytic activity of the the invention. EXAMPLE G Pharmaceutical Composition: Tablets 1000 Tablets Assayed at 5 mg N- [3-hydroxy-2- (7-methoxy-1-naphthyl) propyl] propanamide (Example 1) 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g 10 Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g
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EA200701178A EA012283B1 (en) | 2006-06-30 | 2007-06-29 | New naphthalene derivatives, method of preparing same and pharmaceutical composition containing them |
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CA2593621A CA2593621C (en) | 2006-06-30 | 2007-06-29 | Naphthalene derivatives, process for their preparation and pharmaceutical compositions containing them |
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EP0562956A1 (en) * | 1992-03-27 | 1993-09-29 | Adir Et Compagnie | Naphtylalkylamines, process for their preparation and pharmaceutical compositions containing them |
EP0994102A1 (en) * | 1998-10-12 | 2000-04-19 | Adir Et Compagnie | Cyclic derivatives with a cycloalkylenic chain, process for their preparation and pharmaceutical compositions containing them |
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FR2737725B1 (en) * | 1995-08-08 | 1997-10-31 | Valentonine | NOVEL ACYLATED DERIVATIVES OF MELATONIN AND MELATONINERGIC ANALOGS, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS |
FR2771739B1 (en) * | 1997-11-28 | 2001-04-20 | Adir | NOVEL NAPHTHALENIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
FR2805993B1 (en) * | 2000-03-08 | 2004-01-16 | Adir | USE OF MELATONINERGIC LIGANDS FOR OBTAINING PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF THE DEVELOPMENT OF NITER COMPOUND TOLERANCE |
FR2903101B1 (en) * | 2006-06-30 | 2008-09-26 | Servier Lab | NOVEL NAPHTHALENIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0562956A1 (en) * | 1992-03-27 | 1993-09-29 | Adir Et Compagnie | Naphtylalkylamines, process for their preparation and pharmaceutical compositions containing them |
EP0994102A1 (en) * | 1998-10-12 | 2000-04-19 | Adir Et Compagnie | Cyclic derivatives with a cycloalkylenic chain, process for their preparation and pharmaceutical compositions containing them |
Non-Patent Citations (1)
Title |
---|
MAROT C ET AL: "PHARMACOPHORIC SEARCH AND 3D-QSAR COMPARATIVE MOLECULAR FIELD ANALYSIS STUDIES ON AGONISTS OF MELATONIN SHEEP RECEPTORS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 41, no. 23, 1998, pages 4453 - 4465, XP002172225, ISSN: 0022-2623 * |
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